Acemetacin

Acemetacin is a non-steroidal anti-inflammatory drug and a glycolic acid ester of indometacin that is a cyclooxygenase inhibitor.Target: COXAcemetacin is a non-steroidal anti-inflammatory drug, used for the treatment of osteoarthritis, rheumatoid arthritis, lower back pain, and relieving post-operative pain. Acemetacin, a glycolic acid ester of indometacin, acts as a prodrug; in the body, it is metabolized to indometacin, which then acts as an inhibitor of cyclooxygenase, producing the a

Acemetacin is a carboxylic ester that is the carboxymethyl ester of indometacin. A non-steroidal anti-inflammatory drug, it is used in the treatment of rheumatoid arthritis, osteoarthritis, and low back pain, as well as for postoperative pain and inflammation. Its activity is due to both acemetacin and its major metabolite, indometacin. It has a role as a prodrug, an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is a N-acylindole, a monocarboxylic acid, a carboxylic ester, an indol-3-yl carboxylic acid and a member of monochlorobenzenes. It derives from an indometacin.|Acemetacin is a carboxymethyl ester of indometacin. It is a potent non-steroidal anti-inflammatory drug, derived from the indol-3-acetic acid, whose activity is thought to be mainly through its active metabolite indomethacin. In clinical trials, acemetacin exhibits a better gastric tolerability compared to its active metabolite indometacin. It was developed by E. Merck and Company in Germany as an attempt to provide a safer drug but other than the amelioration on the gastrointestinal effects, the metabolism of acetamicin led to the formation of indomethacin and it kept the same side effects.

Method 1: Using N-(4-methoxyphenyl)-4-chlorobenzohydrazide obtained in the synthesis of indomethacin as raw material and benzyl (3-acetylpropionyloxy)acetate (See Method 3 for its preparation) Cyclization to give [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetoxy] benzyl acetate (I ). The obtained benzyl ester (I) was dissolved in glacial acetic acid and hydrogenated on a palladium-carbon catalyst at room temperature. After hydrogen absorption ceased, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was added to petroleum ether for recrystallization. It is made of exemestine, melting point 149.5～150.5℃, yield 93%. Method 2: Use indomethacin as raw material. Under stirring, 180g (0.503mol) of indomethacin was dissolved in 900ml of anhydrous dimethylformamide, 35g (0.253mol) of finely ground and dried potassium carbonate was added, and stirred at 50°C for 45min. In 15min, 128g (0.56mol) of benzyl bromoacetate was added dropwise and stirred at 50°C for 3h. Filter, concentrate the filtrate, dissolve the residue in chloroform, wash to neutrality with water, and dry over anhydrous sodium sulfate. Concentrate and recrystallize with isopropyl ether-ethyl acetate to obtain 228g of compound (I), yield 89.5%, melting point 96°C. 60g (0.12mol) of compound (I) was dissolved in 700ml of ethyl acetate, 6g of 5% palladium-carbon catalyst was added, hydrogenated at 40°C for 1h, and absorbed about 2.921L of hydrogen (20°C). Filter, concentrate, add petroleum ether (40 ~ 60 ℃) to the residue to complete the crystallization, and put it in the refrigerator for 12h. Filtration, drying in air first, and then vacuum drying, to obtain 46g of aximetene, yield 93%, melting point 150 ~ 153 ℃. Method 3: Use p-methoxyphenylhydrazine and (3-acetylpropionyloxy) benzyl acetate as raw materials. Preparation of (3-acetylpropionyloxy) benzyl acetate. 93.5g (0.68mol) dry potassium carbonate was suspended in 650ml of anhydrous dimethylformamide, heated to 40°C, and 116.1g (1.0mol) 3-acetylpropionic acid was added dropwise within 70min. After the addition is complete, cool to 30°C and add 229.1g (1.0mol) of 2-bromoacetic acid benzyl ester. The reaction was carried out at 50°C for 4h. The inorganic salt was removed by filtration and extracted with toluene. The extract was concentrated, and the residue was dissolved in 400 ml of dichloromethane, washed with water until neutral, and dried over anhydrous sodium sulfate. It was concentrated and the residue was dissolved. 1000 ml of isopropyl ether, add 1500 ml of petroleum ether (40-60 °C) cooled to -25 °C, and place at -15 °C for 1 h. Filtration and vacuum drying at 22°C yielded 235g (3-acetylpropionyloxy) benzyl acetate, yield 89%, melting point 31.5-32.5°C, boiling point 176-178°C/1.20kPa. 26.3g (0.19mo1) of p-methoxyphenylhydrazine was dissolved in 125ml of glacial acetic acid and 450ml of water. Under stirring, 50g (0.19mo1) (3-acetylpropionyloxy) benzyl acetate was added dropwise and stirred for another 1h. It was extracted with toluene, and the extract was washed with water until neutral, dried, and concentrated to obtain 75.5 g of compound (II) as a brown oil, which was directly used in the following reaction. Compound (II) was directly dissolved in 125ml of anhydrous pyridine, 500ml of anhydrous ether was added, and then a solution of 43.5g of p-chlorobenzoyl chloride in 250ml of anhydrous ether was added at 0°C, refluxed under nitrogen for 2h, cooled, washed with water to Neutral, dried and concentrated to obtain 95g of crude compound (III). Without purification, it is directly used in the next reaction. The compound (III) was directly dissolved in 380 ml of acetic acid and heated at 80°C for 5 min. It was concentrated under reduced pressure, and the residue was dissolved in chloroform, washed with sodium bicarbonate solution, and washed with water until neutral. Chromatography with alumina, elution with chloroform. After concentration, it was recrystallized from ether to obtain 10.6 g of compound (I). Based on p-methoxyphenylhydrazine, the yield is 11%. Compound (I) is then reduced to asemestine as in Method 2. Method 4: p-methoxyphenylhydrazine and (3-acetylpropionyloxy) benzyl acetate can also be cyclized first, followed by p-chlorobenzoylation. 45.7g (0.26mo1) p-methoxyphenylhydrazine hydrochloride and 69.2g (0.26mo1) (3-acetylpropionyloxy) benzyl acetate dissolved in 260ml of acetic acid, stirred at 28 ℃ for 42h, then at 50 Stir at ℃ for 5h. After evaporating 150-180 ml of solvent, add 500 ml of ice water and extract with 4×100 ml of toluene. The extracts were combined, washed with potassium bicarbonate solution until acid-free, and dried over anhydrous sodium sulfate. Filter and concentrate to obtain 92g of crude product. After distillation, 76 g of compound (IV) can be obtained with a yield of 80% and a boiling point of 165°C (≤100 Pa). 77.5g (0.44mo1) of p-chlorobenzoyl chloride was dissolved in 275ml of special petroleum (boiling point 180~220℃) and heated to boiling. In 20min, 41g (0.1lmo1) of compound (Ⅳ) was added dropwise. After the addition is complete, heat at 190-195°C for 2 to 3 hours until no hydrogen chloride is released. Cool to 40°C and add 200ml of ether. After crystallization at room temperature, put it in the refrigerator overnight. The crystals were collected by filtration, washed with isopropyl ether, and then recrystallized with ethyl acetate and isopropyl ether to obtain 43.3 g of compound (I) in 78% yield. Compound (I) is then reduced to asemestine as in Method 2.

Anti-inflammatory

Molecular Weight:415.8
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:7
Exact Mass:415.0822650
Monoisotopic Mass:415.0822650
Topological Polar Surface Area:94.8
Heavy Atom Count:29
Complexity:620
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes